Physicians have long recognized that conditions affecting the upper gastrointestinal (GI) tract commonly produce upper abdominal pain, discomfort, abdominal fullness, bloating, early satiety, nausea, heartburn and regurgitation. Such symptoms are typically postprandial and occur either alone or in combination. Overall, upper GI symptoms, including both dyspeptic-type and reflux-type, affect more than 25% of adults in the Western world and have a significant, negative impact on both functional status and sense of individual well-being (Tougas et al., Am J Gastroenterol. 1999; 94: 2845-2854). Symptoms related to disorders of upper gut function are among the most common, presenting complaints in primary-care and GI specialty medical practice. These disorders commonly include GERD (gastroesophageal reflux disease), GERD with erosion, NERD (nonerosive reflux disease), PUD (peptic ulcer disease), FD (functional dyspepsia also indicated as nonulcer dyspepsia), diabetic gastroparesis, gastrointestinal ulcers, Zollinger-Ellison syndrome, and antral G-cell hyperplasia.
Conventional acid suppression therapy includes the use of antacid agents, pepsin inhibitors, gastric mucosa protective agents, anticholine agents for suppressing the secretion of gastric hydrochloric acid, parasympathetic blocking agents, histamine H2 receptor antagonists (hereinafter referred to as “H2 blockers”), proton pump inhibitors, etc. Examples of proton pump inhibitors include Lansoprazole (brand names: Prevacid®, Zoton®, U.S. Pat. No. 4,628,098), Omeprazole (brand names: Losec®, Prilosec®, U.S. Pat. Nos. 4,255,431 and 5,693,818), Pantoprazole (brand names: Protonix®, Somac®, U.S. Pat. No. 4,758,579), Rabeprazole (brand names: Aciphex®, Pariet®, U.S. Pat. No. 5,045,552) and AZD-0865 (Holstein et al., Gastroenterology 2004, 126 (4, Suppl 2): Abst M1436).
Proton pump inhibitors (PPIs) reduce gastric acid secretion by inhibition of the gastric proton pump in parietal cells. However, PPIs and other conventional treatments that reduce gastric acidity do not adequately address all patients. For example, esophagitis may be reduced using proton pump inhibitors, but endoscopy in patients with predominantly reflux-type symptoms reveals that esophagitis may still exist in a minority of patients.
Moreover, patients with predominantly dyspeptic-type symptoms often have no identifiable gross or microscopic lesions in either the esophagus or stomach. Although an anatomic lesion is typically absent in dyspeptic patients, a variety of other abnormalities (e.g., in gastric accommodation, antral motility/emptying and antroduodenal coordination) have been identified and considered to be pathophysiologic, but none is found consistently in all patients. Likewise, attempts to establish an etiologic association between the presence of gastric acid and dyspeptic symptoms has been unsuccessful, even when ambulatory pH monitoring has been employed. Hence, there is no unifying mechanism underlying the generation of symptoms collectively termed “dyspeptic,” including upper abdominal/epigastric pain and discomfort, abdominal fullness, bloating, belching/eructation, early satiety, nausea and/or vomiting.
Upper GI disorders are typically classified by anatomic region, e.g., those of esophageal origin and those of gastroduodenal origin, based on epidemiological evidence pointing to the existence of site-specific clusters of symptoms. However, the GI tract's anatomic continuity and integrated function in digestion and absorption of nutrients makes the separation of symptom clusters by site somewhat artificial. In fact, considering the diaphragm to be an anatomic boundary for defining upper GI disorders, e.g., attributing symptoms localized above the diaphragm such as heartburn to the esophagus, a thoracic organ, and symptoms localized below the diaphragm such as epigastric pain and discomfort to the stomach, an abdominal organ, is not very useful. For example, “heartburn” as the sole or predominant symptom to define gastroesophageal reflux disease (GERD) has very low sensitivity (38%) albeit high specificity (about 90%) (Dent et al., Gut. 2004, 53(May):Supp 4:1-24). Rather than occurring alone as a manifestation of GERD, heartburn is associated with epigastric pain in at least two thirds of patients.
A study comparing the treatment strategies of 500 patients with dyspeptic symptoms (pain or discomfort in the epigastrium with or without heartburn, regurgitation, nausea, vomiting or bloating) shows the difficulty in assessing patients (H. pylori test-and eradicate versus prompt endoscopy) (Lassen et al, Lancet 2000, 356:455-460). Although the main entry criterion was epigastric pain or discomfort, which was reported by all patients, 32% had heartburn and/or regurgitation as their dominant symptom, which was almost as many patients as had dominant epigastric pain (37%). (See Lassen et al.) Therefore, the available data indicate that significant overlap of symptoms exists in esophageal and gastric disorders; GERD patients have dyspeptic symptoms and dyspeptic patients have heartburn and/or regurgitation.
It is estimated that 15-19% of the American population experience symptoms of GERD at least weekly and 10% or more experience associated dyspeptic symptoms. (Locke et al., Gastroenterology 1997, 112 (5):1448-1456) Based on results from the National Ambulatory Medical Care Survey, heartburn and indigestion (dyspepsia) together were estimated to account for over 1.8 million outpatient clinic visits in the United States during the year 2000 (Russo et al, Gastroenterology 2004, 126:1448-1453).
Cholecystokinin (CCK) belongs to the group of substances known as brain-gut peptides and function as a neuropeptide and as a gut hormone. (Noble et al., Pharmacol. Rev. 1999, 51(4):745-781; Crawley et al., Peptides 1994, 15(4):731-755). It is now evident that at least two different receptors, namely CCK1 (formerly CCKA or alimentary) and CCK2 (formerly CCKB or brain) receptors, mediate CCK biological actions. (Noble et al., Pharmacol. Rev., 1999, 51(4):745-781; Woodruff and Hughes, Ann. Rev. Pharmacol. 1991, 31:469-501). CCK1 receptors are found in peripheral tissues, including the GI tract.
CCK is secreted primarily in response to meals and plays a well-recognized role in regulating gallbladder contraction and pancreatic enzyme secretion. Over the last decade, considerable evidence has emerged to support the concept that CCK plays an equally important role in the regulation of motor and sensory functions at various levels of the human upper GI tract. Specifically, the native peptide delays gastric emptying, modulates gastric sensory function (especially in response to fat), increases the rate of meal-induced, transient lower esophageal sphincter relaxations (TLESRs) and affects small bowel and colonic transit.
The CCK1 antagonists loxiglumide and dexloxiglumide have demonstrated the ability to reverse the physiologic effects of CCK on gastric emptying and to decrease dyspeptic symptoms induced by air distension and fat infusion. By example, loxiglumide reduced both exogenous and endogenous CCK-induced delay in gastric emptying of liquids and solids in healthy subjects (Borovicka et al., Am J Physiol. 1996, 271:448-453; Schwizer et al., Gut. 1997, 41(4):500-504). Dexloxiglumide reversed the diminished tolerance to water volume that occurred from CCK release in response to duodenal lipid infusion; the effect was due to reduction of intragastric volume, primarily due to accelerated gastric emptying (Lal et al., Am J Physiol Gastrointest Liver Physiol. 2004, 287(1):72-79). When proximal gastric relaxation was produced in healthy subjects by duodenal infusion of lipid, a potent stimulus of CCK release, the relaxation was reversed by loxiglumide (Feinle et al., Gastroenterology 1996, 110(5):1379-1385). Also, loxiglumide modulated antro-pyloroduodenal dysmotility, which is postulated to play a role in generation of dyspeptic symptoms, after it was experimentally induced in healthy subjects by intraduodenal infusion of a mixed liquid meal (Katschinski et al., Eur J Clin Invest. 1996, 26(7):574-583). Loxiglumide was also able to reverse the lowering of intragastric pressure of healthy subjects after duodenal infusion of lipids induced sensations such as fullness and nausea (See Feinle et al., 1996).
In patients with nonulcer dyspepsia and delayed gastric emptying, loxiglumide was shown to accelerate gastric emptying by comparison to placebo (Chua AS, Bekkering M, et al., 1994). Loxiglumide significantly improved dyspeptic symptoms in patients with non-ulcer dyspepsia in an 8-week study (Chua et al., Ann N Y Acad. Sci. 1994, 713:298-299). In another study in patients with functional dyspepsia, aggravation of nausea, fullness, discomfort, bloating and pain was produced by duodenal infusion of lipid with or without balloon distension; dexloxiglumide significantly improved dyspepsia symptom scores compared to placebo (Feinle et al., Gut. 2001, 48(3): 347-355).
Pharmaceutical compositions comprising CCKB antagonists and a proton pump inhibitor to control gastric acid secretion in gastrointestinal disorders have been described in the literature. (See WO 04/098610, WO 04/101533, WO 04/098609, WO 03/041714, WO 01/90078, WO 01/85724, WO 01/85723, WO 01/85704, WO 01/85167, and WO 93/12817) CCK-B receptors mediate CCK biological actions in the brain and are one of several regulators of gastric acid secretion. It is the CCK1 receptors, however, that mediate the CCK biological actions in peripheral tissues including gastric emptying and esophageal sphincter effects.
In addition, combination therapy of a PPI and a second agent, e.g., loxiglumide, to improve impaired esophageal motility has been disclosed as a possible treatment to gastroesophageal reflux disease. (Tonini et al., Drugs 2004, 64(4): 347-361). International Application Nos. PCT/EP2004/050936 and PCT/EP2005/050336 also disclose pharmaceutical combinations of a proton pump inhibitor and a compound that modifies gastrointestinal motility. Both international applications disclose that dexloxiglumide may be useful for therapy of irritable bowel syndrome (IBS) or GERD and may be used to modify gastrointestinal motility.
However, there is no approved treatment for dyspeptic symptoms associated with gastrointestinal disorders. In addition, there is no convincing evidence that current GI treatments successfully relieve dyspeptic symptoms. While there is compelling evidence for the effectiveness of acid suppression therapy in patients with symptomatic heartburn and/or regurgitation due to GERD, there is a lack of convincing evidence of the effectiveness of acid suppression therapy for dyspeptic symptoms associated with GERD. Indeed, it is a frequent observation that the majority of patients treated with a PPI for GERD symptoms are left with residual dyspeptic symptoms.
Since current acid suppression treatment options for gastrointestinal disorders with dyspepsia type symptoms do not adequately address the complexities of these diseases, there remains a need for a treatment that is effective in at least a substantial portion of this patient population, without producing severe adverse effects.